RESUMEN
We investigated the immunogenic cell death provoked by oxaliplatin (OXA) and the involvement of OXA-induced immunosuppression in colorectal cancer. Immune-proficient or -deficient mice were employed to evaluate the therapeutic effects of OXA. Immunogenic cell death was characterized by cell-surface calreticulin, cytosol-translocated high migration rate group protein B1 (HMGB1), and secretory ATP content. Bone marrow-derived dendritic cell (BMDC) maturation and CD8+ T cell expansion were measured by flow cytometry. Expression of immunosuppressive genes was quantified by both RT-PCR and western blots. The proliferative and apoptotic indexes of xenograft tumors were evaluated by immunohistochemistry and TUNEL assays, respectively. The secretory cytokines were measured with ELISA. OXA induced immunogenic cell death of murine colorectal cancer, which greatly depended on the host immune response. OXA-pretreated CT26 cells promoted BMDC maturation and CD8+ T cell expansion. OXA significantly upregulated indoleamine 2,3-dioxygenase 1 (IDO1) in patient-derived colorectal cancer cells and in combination with the IDO1-specific inhibitor, NLG919, suppressed tumor progression. Simultaneous administration with both OXA and NLG919 greatly promoted CD8+ T cell infiltration and decreased immunosuppressive cytokine transforming growth factor ß (TGF-ß) production, whereas increased immunostimulatory cytokines interleukin (IL)-12p70 and interferon (IFN)-γ. We demonstrated the upregulation of IDO1 by OXA, which combined with the IDO1 inhibitor, tremendously potentiated therapeutic effects of OXA against colorectal cancer.
RESUMEN
BACKGROUND: Circular RNAs are crucial in tumorigenesis. However, little is known about their functions in colorectal cancer (CRC). Circ-SMARCA5 was found to be an oncogene or tumor suppresser in different types of cancers, but its exact role in CRC remains unknown. Here, we aim to identify the role of circ-SMARCA5 in CRC development. METHODS: Circ-SMARCA5 expression was determined by qRT-PCR. CRC cell proliferation, migration, and invasion were detected by CCK-8, wound healing, and Transwell assays, respectively. Bioinformatics analysis was performed to predict target genes. The interaction of microRNA (miR) with circ-SMARCA5 or target genes was detected using luciferase reporter assay. Xenograft model was established to determine the effect of circ-SMARCA5 on CRC tumor growth in vivo. RESULTS: Circ-SMARCA5 expression was dramatically decreased in CRC cell lines and tissues. Circ-SMARCA5 overexpression inhibited CRC cell proliferation, migration and invasion. MiR-93-3p was predicted as a target of circ-SMARCA5 and its overexpression attenuated the anti-tumor effect of circ-SMARCA5 on CRC cells. Furthermore, we predicted AT-rich interaction domain 4B (ARID4B) as the target of miR-39-3p. Functional analysis showed that circ-SMARCA5 upregulated ARID4B expression via miR-39-3p. Additionally, in vivo studies demonstrated that circ-SMARCA5 suppressed CRC tumor progression. CONCLUSION: Circ-SMARCA5 functions as a tumor suppressor by upregulating ARID4B expression via sponging miR-39-3p, and thereby inhibited CRC progression.
Asunto(s)
Adenosina Trifosfatasas/genética , Antígenos de Neoplasias/genética , Proteínas Cromosómicas no Histona/genética , Neoplasias Colorrectales/genética , MicroARNs/genética , Proteínas de Neoplasias/genética , Carcinogénesis/genética , Línea Celular Tumoral , Proliferación Celular , Neoplasias Colorrectales/patología , Progresión de la Enfermedad , Regulación hacia Abajo , Regulación Neoplásica de la Expresión Génica , Humanos , ARN Circular , Regulación hacia ArribaRESUMEN
Background: Colorectal cancer is one of the highly malignant cancers with a poor prognosis. The exact mechanism of colorectal cancer progression is not completely known. Recently, microRNAs (miRNAs, miRs) were suggested to participate in the regulation of multiple cancer development, including colorectal cancer. Methods: MiR-4319 expression in colorectal cancer patient samples was detected by real-time polymerase chain reaction. MiR-4319 was knocked down in the colorectal cancer cells by siRNA transfection to study the role of miR-4319 in the cell cycle and proliferation of colorectal cancer cells. Results: MiR-4319 expression was found to be inverse correlated with survival in colorectal cancer patients. Overexpression of miR-4319 markedly reduced the proliferation of colorectal cancer cells and altered cell cycle distribution. A further experiment showed that ABTB1 is the target gene of miR-4319. MiR-4319 was regulated by PLZF. Conclusion: Our studies indicated that reduced expression of miR-4319 was correlated with poor prognosis in colorectal cancer patients; miR-4319 also suppressed colorectal cancer cell proliferation by targeting ABTB1. ABTB1 might become an excellent therapeutic target for colorectal cancer treatment.